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Osteopontin signaling upregulates cyclooxygenase-2 expression in tumor-associated macrophages leading to enhanced angiogenesis and melanoma growth via α9β1 integrin

Oncogene volume 33, pages 2295–2306 (2014)Cite this article

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A Corrigendum to this article was published on 16 October 2015

Abstract

Tumor-associated macrophages (TAMs) have multifaceted roles in tumor development, particularly linked with tumor angiogenesis and invasion, but the molecular mechanism underlying this association remains unclear. In this study, we report that lack of osteopontin (OPN) suppresses melanoma growth in opn−/− mice and macrophages are the crucial component responsible for OPN-regulated melanoma growth. In tumor microenvironment, OPN activates macrophages and influences angiogenesis by enhancing cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production in an autocrine manner. Furthermore, we identify α9β1 integrin as a functional receptor for OPN that mediates its effect and activates ERK and p38 signaling, which ultimately leads to COX-2 expression in macrophages. The major role played by OPN and PGE2 in angiogenesis are further amplified by upregulation of MMP-9. OPN-activated macrophages promote the migration of endothelial and cancer cells via PGE2. These findings provide evidence that TAMs serve as source of key components such as OPN and COX-2-derived PGE2 and MMP-9 in melanoma microenvironment. Clinical specimens analyses revealed that increased infiltration of OPN-positive TAMs correlate with melanoma growth and angiogenesis. These data provide compelling evidence that OPN and COX-2 expressing macrophages are obligatory factors in melanoma growth. We conclude that OPN signaling is involved in macrophage recruitment into tumor, and our results emphasize the potential role of macrophage in modulation of tumor microenvironment via secretion of OPN, PGE2 and MMP-9, which trigger angiogenesis and melanoma growth. Thus, blockade of OPN and its regulated signaling network provides unique strategy to eradicate melanoma by manipulating TAMs.

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Acknowledgements

We thank Dr B Ramanamurthy, In-charge, Experimental Animal Facility, National Center for Cell Science, Pune, India for breeding and maintaining the Opn−/− mice. We also thank Dr S Ghaskabdi and Dr K Pai, Department of Zoology, University of Pune, India for providing the facility for CAM assay. Skillful assistance was provided by Dr S Vishwakarma, Department of Pathology, YCM Hospital, Pune, India for preparation of Cryosections. The project was supported by Department of Biotechnology (DBT) (GCK), Council of Scientific and Industrial Research (CSIR) (SK and GS), Indian Council of Medical Research (ICMR) (RR) and Department of Science and Technology (DST) (DT), Government of India.

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  1. Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Center for Cell Science, Pune, India

    S Kale, R Raja, D Thorat, G Soundararajan & G C Kundu

  2. Department of Pathology, YCM Hospital, Pune, India

    T V Patil

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Correspondence to G C Kundu.

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Kale, S., Raja, R., Thorat, D. et al. Osteopontin signaling upregulates cyclooxygenase-2 expression in tumor-associated macrophages leading to enhanced angiogenesis and melanoma growth via α9β1 integrin. Oncogene 33, 2295–2306 (2014). https://doi.org/10.1038/onc.2013.184

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